Age-related hearing loss (presbyacusis) is among the most prevalent handicaps in humans over 65 years of age and will become an even greater health problem as population demographics shift towards the elderly. Studies of animal models and of human temporal bones have provided a basic understanding of the histopathologic changes in the aging inner ear. However, there is limited information about the primary cellular injury, the sequence of secondary pathologic changes and the underlying molecular mechanisms leading to loss of auditory function with age. Studies of human presbyacusis have been hindered by the generally poor chemical and structural preservation of most existing temporal bones and lack of premorbid data. This project proposes to addresses basic questions about cellular and molecular changes with age in carefully controlled, prospective studies of human inner ears processed optimally to meet the objectives of each specific aim. Aim 3.1 will seek further knowledge of histopathologic alterations in the aging ear and provide morphometric data on structural changes in the lateral wall and primary auditory neurons for correlation with premorbid behavioral and physiologic measures of auditory function. Aim 3.2 will extend knowledge to the human inner ear about the distribution and age- related alterations in the expression patterns of key structural, ion transport, metabolic and regulatory proteins. Aim 3.3 will evaluated candidate genes that are likely to under- or over-expressed with age in the human inner year using real-time quantitative RT-PCR and will identify novel candidate genes by DNA microarray screening analysis. Genes shown to be differentially expressed with age will then be characterized at the cell and tissue level either by immunostaining for their protein products or through use of in situ hybridization to localize mRNA. Ultimately knowledge gained through this project will be translatable into pharmacologic and genetic interventions to prevent or delay age-related deterioration of auditory function.